Resident in adult bone marrow is a cell population referred to as marrow stromal cells (MSCs) that possess several unique properties. First, MSCs mediate various aspects of hematopoiesis by expressing matrix molecules, cytokines and cell-surface receptors that provide architecture to the hematopoietic organ, support granulopoiesis and lymphopoiesis, and maintain the multi-potency of the hematopoietic stem cell. Second, MSCs are also able to differentiate into a variety of mesenchymal cell lineages, including osteoblasts and chondrocytes, suggesting the cells participate in most aspects of bone growth and repair. Accordingly, the potential of MSCs as cell and/or gene therapy vectors for the treatment of connective tissue diseases is being intensively studied. Such efforts have culminated in the first human clinical trial using MSCs to treat Osteogenesis Imperfecta. While the relevance of using MSCs to treat connective tissue diseases is obvious, our recent data regarding intracranial transplantation of MSCs suggests the cells may be useful vectors to treat central nervous system (CNS) disorders, as well. We recently showed that following injection into neonatal mouse brains, murine MSCs undergo marked expansion, migrate along established white matter tracts throughout successive layers of the brain, and at a low frequency adopt glial and possibly neuronal cell fates. Therefore, MSCs respond to the microenvironment of the developing brain in a manner similar to neural progenitor cells. To explore this potential of MSCs further, we propose to compare and contrast the engraftment, proliferation, migration, and differentiation of MSCs following injection into embryonic, neonatal, or adult brain with particular emphasis on 1) quantitating the number of MSCs that persist in brain as a function of time, 2) mapping their anatomical locations, and 3) characterizing their phenotype. By analyzing how brain development affects MSC engraftment, we can optimize a transplantation regimen that translates into an effective clinical strategy for using MSCs to treat CNS disorders. To directly assess the therapeutic potential of MSCs, we will transplant the cells into the brains of mice afflicted with Mucopolysaccharidosis Type VII, which exhibit progressive CNS neurodegeneration. These experiments will be conducted in a maimer so that they provide a basis for using a patients own MSCs to treat disorders affecting the CNS.